Tomasz A. Timek

Experimental and clinical assessment of mitral annular area and dynamics: what are we actually measuring?

The mitral annulus is an essential, dynamic, and tightly coupled component of the mitral valve/left atrial/left ventricular complex that aids in effective and efficient valve closure and unimpeded left ventricular filling. Although the dynamic nature of mitral annular motion has been studied carefully for more than 30 years, accurate measurement of mitral annular area and motion continues to be a challenge for physiologists and clinicians alike. Roentgenographic ciné imaging of radiopaque markers, sonomicrometry, magnetic resonance imaging, and two-dimensional echocardiography have all been used to evaluate mitral annular area and dynamics, yet widely disparate measurements abound. Paradoxically, newer three-dimensional transesophageal echocardiographic findings may have added to this miasma. To explore the variability of these measurements, we reviewed our experimental data as well as clinical and experimental observations reported in the literature to clarify what we are actually measuring and perhaps explain the reported disagreement. The objective was to shed some light on the possible reasons for these discordant findings.

The Effect of AlloDerm Envelopes on Periprosthetic Capsule Formation with and without Radiation

Background: The pathobiology of radiation-induced periprosthetic capsular formation and factors that may ameliorate its development have not been fully elucidated. The authors hypothesized that AlloDerm would diminish radiation-induced capsular formation. Methods: Two 5-ml implants were placed submuscularly in the backs of 41 rats. The right implant was wrapped with AlloDerm and the left remained bare. After 48 hours, 20 animals underwent irradiation to each implant, and 21 animals underwent no further treatment and served as controls. After 3 and 12 weeks, the capsules were harvested and submitted for tensile strength and histologic examination. Intraprosthetic pressures were measured in each implant at the time of surgery and when the animals were killed. Results: The intraprosthetic pressure decrease was uniform among all groups at 3 and 12 weeks. Between 3 and 12 weeks, capsular tensile strength increased in nonirradiated bare implants. There was considerable invasion of nonirradiated AlloDerm by inflammatory infiltrates at 3 weeks, and AlloDerm thickness decreased over time. Cellular invasion of AlloDerm was decreased with irradiation at both time points. Capsular tensile strength and thickness of the irradiated bare and AlloDerm capsules did not change between 3 and 12 weeks. Radiation increased inflammation of bare capsules at 12 weeks, but it was significantly reduced in irradiated AlloDerm capsules. The majority of irradiated bare capsules developed pseudoepithelium, whereas AlloDerm protected capsules from this transformation. Conclusion: AlloDerm decreases radiation-related inflammation and delays or diminishes pseudoepithelium formation and thus may slow progression of capsular formation, fibrosis, and contraction.

Mitral Leaflet Remodeling in Dilated Cardiomyopathy

Background— Normal mammalian mitral leaflets have regional heterogeneity of biochemical composition, collagen fiber orientation, and geometric deformation. How leaflet shape and regional geometry are affected in dilated cardiomyopathy is unknown. Methods and Results— Nine sheep had 8 radio-opaque markers affixed to the mitral annulus (MA), 4 markers sewn on the central meridian of the anterior mitral leaflet (AML) forming 4 distinct segments S1 to S4 and 2 on the posterior leaflet (PML) forming 2 distinct segments S5 and S6. Biplane videofluoroscopy and echocardiography were performed before and after rapid pacing (180 to 230 bpm for 15±6 days) sufficient to develop tachycardia-induced cardiomyopathy (TIC) and functional mitral regurgitation (FMR). Leaflet tethering was defined as change of displacement of AML and PML edge markers from the MA plane from baseline values while leaflet length was obtained by summing the segments between respective leaflet markers. With TIC, total AML and PML length increased significantly (2.11±0.16 versus 2.43±0.23 cm and 1.14±0.27 versus 1.33±0.25 cm before and after pacing for AML and PML, respectively; P<0.05 for both), but only segments near the edge of each leaflet (S4 lengthened by 23±17% and S5 by 24±18%; P<0.05 for both) had significant regional remodeling. AML shape did not change and no leaflet tethering was observed. Conclusion— TIC was not associated with leaflet tethering or shape change, but both anterior and posterior leaflets lengthened because of significant remodeling localized near the leaflet edge. Leaflet remodeling accompanies mitral regurgitation in cardiomyopathy and casts doubt on FMR being purely “functional” in etiology.

Influence of Anterior Mitral Leaflet Second-Order Chordae Tendineae on Left Ventricular Systolic Function

Background—The contribution of anterior mitral leaflet second-order (“strut”) chordae tendineae to left ventricular (LV) systolic mechanics is debated; we measured the in vivo contribution of anterior chordae tendineae (ACT) and posterior chordae tendineae (PCT) to regional and global LV contractile function. Methods and Results—Eight sheep had radiopaque markers implanted in the LV epicardium, partitioning the ventricle into 12 regions. Microminiature force transducers and snares were sutured to anterior leaflet “strut” chordae originating from ACT and PCT papillary muscles. Chordal tension, marker images, and hemodynamic data were acquired before and after (CUT) severing ACT and PCT. Fractional area shrinkage and slope of the regional end-diastolic area–regional stroke work relation (r-PRSW) were computed for each LV region. CUT did not affect global LV systolic function but reduced FAS in LV segments near the PCT insertion site: equatorial posterior lateral (19±2% versus 16±2%, P <0.05), apical posterior lateral (23±4% versus 19±4%, P <0.05), and posterior medial LV segments (16±2% versus 13±2%, P <0.05). r-PRSW fell near both the ACT (equatorial anterior medial [84±8 versus 62±11 mm Hg, P <0.05] and lateral [73±7 versus 53±9 mm Hg, P <0.05]) and PCT (apical posterior medial [91±12 versus 67±17 mm Hg, P <0.05] and lateral [72±8 versus 59±9 mm Hg, P <0.05]) LV insertion sites. Maximum tension in PCT was higher than in ACT (0.81±0.1 versus 0.52±0.08 N, P <0.01). Conclusions—Dividing anterior leaflet strut chordae in sheep was associated acutely with regional LV systolic dysfunction near the chordal insertion sites. Caution is necessary when embarking on procedures that cut second-order chordae to treat ischemic mitral regurgitation, since this may compromise LV systolic function in ventricles that are already impaired.

Ring annuloplasty prevents delayed leaflet coaptation and mitral regurgitation during acute left ventricular ischemia

OBJECTIVE Incomplete mitral leaflet coaptation during acute left ventricular ischemia is associated with end-diastolic mitral annular dilatation and ischemic mitral regurgitation. Annular rings were implanted in sheep to investigate whether annular reduction alone is sufficient to prevent mitral regurgitation during acute posterolateral left ventricular ischemia. METHODS Radiopaque markers were inserted around the mitral anulus, on papillary muscle tips, and on the central meridian of both mitral leaflets in three groups of sheep: control (n = 5), Physio ring (n = 5) (Baxter Cardiovascular Div, Santa Ana, Calif), and Duran ring (n = 6) (Medtronic Heart Valve Div, Minneapolis, Minn). After 8 +/- 1 days, animals were studied with biplane videofluoroscopy before and during left ventricular ischemia. Annular area was calculated from 3-dimensional marker coordinates and coaptation defined as minimal distance between leaflet edge markers. RESULTS Before ischemia, leaflet coaptation occurred just after end-diastole in all groups (control 17 +/- 41, Duran 33 +/- 30, Physio 33 +/- 24 ms, mean +/- SD, P >.2 by analysis of variance). During ischemia, regurgitation was detected in all control animals, and leaflet coaptation was delayed to 88 +/- 8 ms after end-diastole (P =.02 vs preischemia). This was associated with increased end-diastolic annular area (8.0 +/- 0.9 vs 6.7 +/- 0.6 cm(2), P =.004) and septal-lateral annular diameter (2.9 +/- 0.1 vs 2.5 +/- 0.1 cm, P =.02). Mitral regurgitation did not develop in Duran or Physio sheep, time to coaptation was unchanged (Duran 25 +/- 25 ms, Physio 30 +/- 48 ms [both P >.2 vs preischemia]), and annular area remained fixed. CONCLUSION Mitral annular area reduction and fixation with an annuloplasty ring eliminated delayed leaflet coaptation and prevented mitral regurgitation during acute left ventricular ischemia after ring implantation.

Edge-to-edge mitral valve repair without ring annuloplasty for acute ischemic mitral regurgitation

BackgroundAlfieri edge-to-edge mitral repair has been used clinically with ring annuloplasty to correct ischemic mitral regurgitation (IMR), but its efficacy without concomitant ring annuloplasty has not been described in this setting. MethodsSeventeen sheep underwent implantation of 9 radiopaque markers on the left ventricle, 8 on the mitral annulus (MA), 1 on each papillary muscle (PM) tip, and 1 on the anterior and posterior leaflet edges near the anterior and posterior commissures. Alfieri repair was performed in 7 animals, and 10 were controls. Biplane videofluoroscopy and transesophageal echocardiography (TEE) were performed (open chest) before and continuously during left circumflex coronary artery occlusion to induce acute IMR. MA area (MAA), anterior (APM), and posterior (PPM) papillary muscle tip distances to midseptal MA (“saddle horn”), and distance of each leaflet marker to the mitral annular plane were calculated from 3-dimensional marker coordinates at end-systole (ES). ResultsSeverity of IMR was not different between groups (+1.9±0.7 versus +1.4±0.5 for Control and Alfieri, respectively; P =not significant [NS]). Mitral annular area (MAA; 21±15 versus 19±9%; P =NS) and septal-lateral (SL) annular diameter (12±6 versus 12±11%; P =NS) increased similarly during ischemia. While PPM-saddle horn distance increased in both groups (1.5±1.3 and 1.6±1.4 mm for Control and Alfieri, respectively; P <0.05 versus preischemia), APM-saddle horn distance increased in Control (1.0±1.2 mm; P =0.03) but not in the Alfieri animals (0.8±08 mm; P =0.07). Leaflet edge displacements from the annular plane during ischemia were similar in both groups. ConclusionsAlfieri repair did not prevent acute IMR nor alter ischemic valvular or subvalvular geometric perturbations. Adjunct surgical procedures, such as ring annuloplasty, are also necessary.

Edge-to-edge mitral repair: gradients and three-dimensional annular dynamics in vivo during inotropic stimulation

OBJECTIVE The edge-to-edge (Alfieri) mitral repair technique appears to be clinically promising, but the potential for functional mitral stenosis, especially with exercise, remains a concern. We used the myocardial marker method combined with Doppler echocardiography to evaluate mitral annular (MA) three-dimensional (3-D) dynamics and transvalvular gradients after leaflet approximation before and during dobutamine infusion. METHODS Eight adult sheep underwent implantation of eight myocardial markers around the MA and nine in the left ventricle. Mitral leaflet edges were approximated at the valve center and micromanometers were placed in the left ventricle and atrium. The animals were studied with biplane videofluoroscopy to determine 3-D marker coordinates for computation of precise 3-D MA area and left ventricular (LV) volume. Epicardial Doppler echocardiography measured peak and mean diastolic mitral valve gradients at baseline and during dobutamine infusion (10 microg/kg per min). RESULTS During dobutamine stimulation, left ventricular dP/dt increased from 1776+/-712 to 3390+/-618 mmHg/s (P=0.002), and cardiac output (CO) increased from 2.7+/-1.1 to 5.1+/-1.2 l/min (P=0.009). Mitral annular area (MAA) at end-diastole (ED) fell from 8.6+/-1.4 to 7.0+/-1.8 cm(2) (P=0.001) with inotropic stimulation, but only a modest increase was observed in mean (1.4+/-0.4 vs. 2.4+/-1.0 mmHg, P=0.046) and peak (2.7+/-0.8 vs. 4.9+/-2.5 mmHg, P=0.03) diastolic mitral valve gradients. MAA changed dynamically throughout the cardiac cycle, reflecting normal physiology, but the magnitude of MAA change was augmented during inotropic stimulation (18+/-5% and 27+/-4% for control and dobutamine, respectively; P=0.004). CONCLUSION Dobutamine increased CO by 89% and decreased ED annular area by 19% after edge-to-edge repair, yet only a small increase in valve gradient occurred. Marker analysis showed enhanced dynamic motion of the mitral annulus. Thus, the edge-to-edge mitral valve repair was not associated with substantial transvalvular obstruction during high flow conditions and did not perturb normal MA 3-D dynamics in normal ovine hearts.

The effect of pure mitral regurgitation on mitral annular geometry and three-dimensional saddle shape

OBJECTIVE Chronic ischemic mitral regurgitation is associated with mitral annular dilatation in the septal-lateral dimension and flattening of the annular 3-dimensional saddle shape. To examine whether these perturbations are caused by the ischemic insult, mitral regurgitation, or both, we investigated the effects of pure mitral regurgitation (low pressure volume overload) on annular geometry and shape. METHODS Eight radiopaque markers were sutured evenly around the mitral annulus in sheep randomized to control (CTRL, n = 8) or experimental (HOLE, n = 12) groups. In HOLE, a 3.5- to 4.8-mm hole was punched in the posterior leaflet to generate pure mitral regurgitation. Four-dimensional marker coordinates were obtained radiographically 1 and 12 weeks postoperatively. Mitral annular area, annular septal-lateral and commissure-commissure dimensions, and annular height were calculated every 16.7 ms. RESULTS Mitral regurgitation grade was 0.4 +/- 0.4 in CTRL and 3.0 +/- 0.8 in HOLE (P < .001) at 12 weeks. End-diastolic left ventricular volume index was greater in HOLE at both 1 and 12 weeks; end-systolic volume index was larger in HOLE at 12 weeks. Mitral annular area increased in HOLE predominantly in the commissure-commissure dimension, with no difference in annular height between HOLE versus CTRL at 1 or 12 weeks, respectively. CONCLUSION In contrast with annular septal-lateral dilatation and flattening of the annular saddle shape observed with chronic ischemic mitral regurgitation, pure mitral regurgitation was associated with commissure-commissure dimension annular dilatation and no change in annular shape. Thus, infarction is a more important determinant of septal-lateral dilatation and annular shape than mitral regurgitation, which reinforces the need for disease-specific designs of annuloplasty rings.

The effects of mitral annuloplasty rings on mitral valve complex 3-D geometry during acute left ventricular ischemia

OBJECTIVE Annuloplasty rings are used to treat ischemic mitral regurgitation (IMR), but their exact effects on 3-D geometry of the overall mitral valve complex during acute left ventricular (LV) ischemia remain unknown. METHODS Radiopaque markers were sutured to the mitral leaflet edges, annulus, papillary muscle tips, and ventricle in three groups of sheep. One group served as control (n = 5), and the others underwent Duran (n = 6) or Physio (n = 5) ring annuloplasty. One week later, 3-D marker coordinates at end-systole were obtained before and during balloon occlusion of the circumflex artery. RESULTS In all control animals, acute LV ischemia was associated with: (i) septal-lateral separation of the leaflet edges, which was predicted by lateral displacement of the lateral annulus during septal-lateral mitral annular dilatation; (ii) apical restriction of the posterior leaflet edge, which was predicted by displacement of the lateral annulus away from the non-ischemic anterior papillary muscle; (iii) displacement of the posterior papillary muscle, which was not predictive of either septal-lateral leaflet separation or leaflet restriction; and (iv) mitral regurgitation. In the Duran group during ischemia, the posterior leaflet edge shifted posteriorly due to posterior movement of the lateral annulus, but no IMR occurred. In the Physio group during ischemia, neither the posterior leaflet edge nor the lateral annulus changed positions, and there was no IMR. In both the Duran and Physio groups, displacement of the posterior papillary muscle did not lead to IMR. CONCLUSIONS Either annuloplasty ring prevented the perturbations of mitral leaflet and annular--but not papillary muscle tip--3-D geometry during acute LV ischemia. By fixing the septal-lateral annular dimension and preventing lateral displacement of the lateral annulus, annuloplasty rings prevented systolic septal-lateral leaflet separation and posterior leaflet restriction, and no acute IMR occurred. The flexible ring allowed posterior displacement of the posterior leaflet edge and the lateral annulus, which was not observed with a semi-rigid ring.

Significant Changes in Mitral Valve Leaflet Matrix Composition and Turnover With Tachycardia-Induced Cardiomyopathy

Background— Dilated cardiomyopathy (DCM) involves significant remodeling of the left ventricular–mitral valve (MV) complex, but little is known regarding the remodeling of the mitral leaflets. The aim of this study was to assess changes in matrix composition and turnover in MV leaflets with DCM. Methods and Results— Radiopaque markers were implanted in 24 sheep to delineate the MV; 10 sheep underwent tachycardia-induced cardiomyopathy (TIC), whereas 14 sheep remained as controls. Biplane videofluoroscopy was performed before and after TIC. Immunohistochemistry was performed on leaflet cross-sections taken from the septal, lateral, anterior, and posterior commissures attachment segments. Staining intensity was quantified within each attachment segment and leaflet region (basal, mid-leaflet, and free edge). Mitral regurgitation increased from 0.2±0.4 before TIC to 2.2±0.9 after TIC (P<0.0002). TIC leaflets demonstrated significant remodeling compared to controls, including greater cell density and loss of leaflet layered structure (all P<0.05). Collagen and elastic fiber turnover was greater in TIC, as was the myofibroblast phenotype (all P<0.05). Compositional differences between TIC and control leaflets were heterogeneous by annular segment and leaflet region, and related to regional changes in leaflet segment length with TIC. Conclusions— This study shows that the MV leaflets are significantly remodeled in DCM with changes in leaflet composition, structure, and valve cell phenotype. Understanding how alterations in leaflet mechanics, such as those induced by DCM, drive cell-mediated remodeling of the extracellular matrix will be important in developing future treatment strategies.